Cushing's disease, due to an ACTH-secreting pituitary tumor, causes illness due to excess steroid production; no suitable drug therapies are available, and surgical excision, is not always curative. We have demonstrated that ACTH-secreting pituitary tumors express abundant peroxisome proliferators activated receptor-gamma (PPAR-gamma). PPAR-gamma and the retinoid X receptor (RXR) form a permissive heterodimer, that can be activated by either PPAR-gamma and/ or RXR-specific ligands to regulate target gene transcription. Several natural occurring and synthetic PPAR-gamma ligands, including the thiazolidinedione (TZD), rosiglitazone; the non-TZD, GW7845; and the triterpenoid, cyano-3,12- dioxooleaneana-1,9(11)-dien-28-oyl]imidazole (CDDO-IM) bind PPAR-gamma, to regulate multiple actions. PPAR-gamma activation plays a critical role in adipogenesis, glucose metabolism, and placental function, and TZD's are widely used to treat diabetes. Treatment of human and mouse corticotroph pituitary tumor cells in vitro with PPAR-gamma ligands, inhibited tumor growth, and induced corticotroph tumor apoptosis. When athymic Nu/ Nu mice harboring subcutaneous xenografted corticotroph tumors, were treated with rosiglitazone, 4 of 5 treated mice did not develop tumors. Furthermore, plasma ACTH and corticosterone hormone levels were lower in rosiglitazone-treated animals. In addition, rosiglitazone, given to two patients with Cushing's disease, decreased 24 hour urinary cortisol levels by approximately 55% in one patient, and normalized cortisol levels in the second patient. Recently, we have demonstrated potent anti-proliferative, and pro-apoptotic actions of the PPAR-gamma ligand CDDO-IM in corticotroph tumor cells, using 1000-fold lower concentrations than rosiglitazone. This project will examine the chemopreventative actions of CDDO-IM in vivo in the Rb heterozygote knock-out mouse that develops spontaneous pituitary corticotroph tumor. We will also examine the effects of a high fat diet on pituitary corticotroph tumor development, and examine the role of chemopreventative anti-inflammatory treatment with CDDO-IM in the corticotroph tumor model. Our ultimate goal is to develop a rationale for clinical application of these PPAR-gamma ligands as a novel medical therapy in Cushing's disease.